Early, precise, and safe clinical evaluation of the pharmacodynamic effects of novel agents in the intact human tumor microenvironment.

Introduction: Drug development is systemically inefficient. Research and development costs for novel therapeutics average hundreds of millions to billions of dollars, with the overall likelihood of approval estimated to be as low as 6.7% for oncology drugs. Over half of these failures are due to a lack of drug efficacy. This pervasive and repeated low rate of success exemplifies how preclinical models fail to adequately replicate the complexity and heterogeneity of human cancer. Therefore, new methods of evaluation, early in the development trajectory, are essential both to rule-in and rule-out novel agents with more rigor and speed, but also to spare clinical trial patients from the potentially toxic sequelae (high risk) of testing investigational agents that have a low likelihood of producing a response (low benefit). Methods: The clinical in vivo oncology (CIVO®) platform was designed to change this drug development paradigm. CIVO precisely delivers microdose quantities of up to 8 drugs or combinations directly into patient tumors 4-96 h prior to planned surgical resection. Resected tissue is then analyzed for responses at each site of intratumoral drug exposure. Results: To date, CIVO has been used safely in 6 clinical trials, including 68 subjects, with 5 investigational and 17 approved agents. Resected tissues were analyzed initially using immunohistochemistry and in situ hybridization assays (115 biomarkers). As technology advanced, the platform was paired with spatial biology analysis platforms, to successfully track anti-neoplastic and immune-modulating activity of the injected agents in the intact tumor microenvironment. Discussion: Herein we provide a report of the use of CIVO technology in patients, a depiction of the robust analysis methods enabled by this platform, and a description of the operational and regulatory mechanisms used to deploy this approach in synergistic partnership with pharmaceutical partners. We further detail how use of the CIVO platform is a clinically safe and scientifically precise alternative or complement to preclinical efficacy modeling, with outputs that inform, streamline, and de-risk drug development.

Perivascular Epithelioid Cell-Family Tumors in Children, Adolescents and Young Adults:Clinicopathologic Features in 70 Cases.

CONTEXT.­: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors of uncertain histogenesis expressing smooth muscle and melanocytic markers. The clinicopathologic spectrum in young patients is not well documented. OBJECTIVE.­: To describe a multi-institutional series of PEComas in children, adolescents, and young adults. DESIGN.­: PEComas, not otherwise specified (NOS); angiomyolipomas (AMLs); lymphangioleiomyomatosis; and clear cell sugar tumors were retrospectively identified from 6 institutions and authors' files. RESULTS.­: Seventy PEComas in 64 patients (median age, 15 years) were identified. They were more common in females (45 of 64 patients), occurring predominately in kidney (53 of 70), followed by liver (6 of 70). Thirty-four patients had confirmed tuberous sclerosis complex (TSC), 3 suspected TSC mosaicism, 2 Li-Fraumeni syndrome (LFS) and 1 neurofibromatosis type 1. Most common variants were classic (49 of 70) and epithelioid (8 of 70) AML. Among patients with AMLs, most (34 of 47) had TSC, and more TSC patients had multiple AMLs (15 of 36) than non-TSC patients (2 of 13). Two TSC patients developed malignant transformation of classic AMLs: 1 angiosarcomatous and 1 malignant epithelioid. Lymphangioleiomyomatosis (5 of 70) occurred in females only, usually in the TSC context (4 of 5). PEComas-NOS (6 of 70) occurred exclusively in non-TSC patients, 2 of whom had LFS (2 of 6). Three were malignant, 1 had uncertain malignant potential, and 2 were benign. All 4 PEComas-NOS in non-LFS patients had TFE3 rearrangements. CONCLUSIONS.­: Compared to the general population, TSC was more prevalent in our cohort; PEComas-NOS showed more frequent TFE3 rearrangements and possible association with LFS. This series expands the spectrum of PEComas in young patients and demonstrates molecular features and germline contexts that set them apart from older patients.

The Pathologic Diagnosis of Pediatric Soft Tissue Tumors in the Era of Molecular Medicine: The Sarcoma Pediatric Pathology Research Interest Group Perspective.

CONTEXT.­: Pediatric soft tissue tumors are one of the areas of pediatric pathology that frequently generate consult requests. Evolving classification systems, ancillary testing methods, new treatment options, research enrollment opportunities, and tissue archival processes create additional complexity in handling these unique specimens. Pathologists are at the heart of this critical decision-making, balancing responsibilities to consider expediency, accessibility, and cost-effectiveness of ancillary testing during pathologic examination and reporting. OBJECTIVE.­: To provide a practical approach to handling pediatric soft tissue tumor specimens, including volume considerations, immunohistochemical staining panel recommendations, genetic and molecular testing approaches, and other processes that impact the quality and efficiency of tumor tissue triage. DATA SOURCES.­: The World Health Organization Classification of Soft Tissue and Bone Tumors, 5th edition, other recent literature investigating tissue handling, and the collective clinical experience of the group are used in this manuscript. CONCLUSIONS.­: Pediatric soft tissue tumors can be difficult to diagnose, and evaluation can be improved by adopting a thoughtful, algorithmic approach to maximize available tissue and minimize time to diagnosis.

Myxoid epithelioid smooth muscle tumor of the vulva: A distinct entity with MEF2D::NCOA2 gene fusion.

Smooth muscle tumors are the most common mesenchymal tumors of the female genital tract, including the vulva. Since vulvar smooth muscle tumors are rare, our understanding of them compared to their uterine counterparts continues to evolve. Herein, we present two cases of morphologically distinct myxoid epithelioid smooth muscle tumors of the vulva with novel MEF2D::NCOA2 gene fusion. The tumors involved 24 and 37-year-old women. Both tumors presented as palpable vulvar masses that were circumscribed, measuring 2.8 and 5.1 cm in greatest dimension. Histologically, they were composed of epithelioid to spindle-shaped cells with minimal cytologic atypia and prominent myxoid matrix. Rare mitotic figures were present (1-3 mitotic figures per 10 high-power field (HPF)), and no areas of tumor necrosis were identified. By immunohistochemistry, the neoplastic cells strongly expressed smooth muscle actin, calponin, and desmin, confirming smooth muscle origin. Next-generation sequencing identified identical MEF2D::NCOA2 gene fusions. These two cases demonstrate that at least a subset of myxoid epithelioid smooth muscle tumors of the vulva represent a distinct entity characterized by a novel MEF2D::NCOA2 gene fusion. Importantly, recognition of the distinct morphologic and genetic features of these tumors is key to understanding the biological potential of these rare tumors.

Rhabdomyosarcoma: Updates on classification and the necessity of molecular testing beyond immunohistochemistry.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents under the age of 20. The current World Health Organization (WHO) classification for soft tissue and bone tumors recognizes 4 distinct subtypes of RMS based on clinicopathological and molecular genetic features: embryonal, alveolar, spindle cell/sclerosing and pleomorphic subtypes. However, with the increased use of molecular techniques, the classification of rhabdomyosarcoma has been evolving rapidly. New subtypes such as osseus RMS harboring TFCP2/NCOA2 fusions or RMS arising in inflammatory rhabdomyoblastic tumor have been emerging within the last decade, adding to the complexity of diagnosing skeletal muscle tumors. This review article provides an overview of classically recognized distinctive subtypes as well as new, evolving subtypes and discusses important morphologic, immunophenotypic and molecular genetic features of each subtype including recommendations for a diagnostic approach of malignant skeletal muscle neoplasms.

Anterior mediastinal neuroblastoma in an adult: an additional case of a rare tumor in an unusual location with review of the literature.

Neuroblastoma is rare in the adult population, especially in thoracic or mediastinal locations, with only 25 previously reported cases. We report an additional example of primary thymic neuroblastoma in a previously asymptomatic 71-year-old man with an anterior mediastinal mass who underwent robotic excision with pericardium and adjacent lung. The tumor was a 5.2 cm partially encapsulated, white-tan and rubbery mass with grossly identifiable areas of necrosis (25%) and hemorrhage. Histologically, the specimen showed a rim of adipose tissue and residual thymic tissue with areas of cystic thymic epithelium and prominent lymphoid tissue containing Hassall's corpuscles. The tumor was composed of uniform, round cells with scant cytoplasm and small nuclei with inconspicuous nucleoli set within a background of conspicuous neuropil. Mitotic figures were easily found. By immunohistochemistry, the tumor cells expressed synaptophysin, chromogranin, NKX2.2 (diffuse, nuclear), GFAP (patchy), SMI31 (neurofilament) (focal, cytoplasmic), and TdT (diffuse, nuclear), while lacking expression of CD99, TTF-1, CK 20, MCPyV, PHOX2B, Olig2, OCT3/4, CD45, CD3 and PAX5. S100 protein was negative in the neuroblastic cells, with scattered positive cells in a vague sustentacular-like pattern. Fluorescence in situ hybridization for isochromosome 12p and EWSR1 gene rearrangement were negative. As thymic neuroblastoma is extremely rare in adults, a neuroblastic tumor of germ cell origin (either primary or metastatic) or spread from a sinonasal tract tumor should be excluded because of differing treatments and prognoses. The properties of these rare neoplasms appear similar to olfactory neuroblastoma rather than pediatric-type neuroblastoma.

ALK-Rearranged Epithelioid Mesenchymal Neoplasm: Expanding the Spectrum of Tyrosine Kinase-Altered Mesenchymal Tumors.

The anaplastic lymphoma kinase (ALK) gene encodes a receptor tyrosine kinase, and fusions involving this gene have been reported in a variety of mesenchymal neoplasms. ALK-altered tumors with epithelioid morphology have been described in epithelioid inflammatory myofibroblastic sarcoma and epithelioid fibrous histiocytoma. Herein, we describe the clinicopathologic features of 7 ALK-rearranged mesenchymal tumors with epithelioid morphology occurring predominately in the pediatric population. Tumors occurred in 4 females and 3 males with an age ranging from 1 month to 28 years. Five tumors were superficial and solitary, while 1 presented with multiple peritoneal/omental nodules, and 1 presented as a large mediastinal mass. Morphologically, all tumors comprised epithelioid cells arranged in sheets, anastomosing cords, or small clusters embedded in a myxohyaline stroma. The cells had slightly variably sized ovoid nuclei with moderately prominent nucleoli and abundant eosinophilic cytoplasm. Four cases had sparse mitotic figures without necrosis. The remaining 3 tumors (2 deep and 1 superficial) had more than 10 mitoses per 10 high-power fields as well as foci of necrosis. ALK fusions were identified in all cases. The fusion partners included HMBOX1 (n = 1), VCL (n = 1), PRRC2B (n = 1), MYH10 (n = 1), STRN (n = 1), and EML4 (n = 2). One tumor recurred locally 2 years after initial resection; 1 patient had widely metastatic disease (mediastinal tumor). At the time of last follow-up (n = 6), 4 patients were alive without evidence of disease, 1 died due to complications of therapy (peritoneal tumor), and 1 was alive with disease. Our findings expand the spectrum of ALK-rearranged mesenchymal tumors. Our cases predominately occurred in older children and mainly exhibited epithelioid to round cell morphology, as opposed to spindle cell morphology. We also show that tumors in a deep location with higher-grade features follow a more aggressive clinical course.

Intraosseous Spindle Cell Rhabdomyosarcoma with MEIS1::NCOA2 Fusion - Case Report with Substantial Clinical Follow-up and Review of the Literature.

Spindle cell/sclerosing rhabdomyosarcoma (SSRMS) is a clinicopathologically and molecularly heterogeneous disease. Gene fusions have been identified in intraosseous SSRMS, consisting predominantly of EWSR1/FUS::TFCP2 and MEIS1::NCOA2. The former often follow an aggressive clinical course; there is limited clinical follow-up available for the latter. We report here a new case of the very rare intraosseous SSRMS with MEIS1::NCOA2 gene fusion and include the detailed treatment course and 52 months of clinical follow-up. SSRMS with MEIS1::NCOA2 gene fusion appears biologically distinct from other intraosseous SSRMS, following a course characterized by local recurrence with rare reports of metastasis to date.

Outcomes After Preoperative Chemoradiation With or Without Pazopanib in Non-Rhabdomyosarcoma Soft Tissue Sarcoma: A Report From Children's Oncology Group and NRG Oncology.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.ARST1321 was a phase II study designed to compare the near complete pathologic response rate after preoperative chemoradiation with/without pazopanib in children and adults with intermediate-/high-risk chemotherapy-sensitive body wall/extremity non-Rhabdomyosarcoma Soft Tissue Sarcoma (ClinicalTrials.gov identifier: NCT02180867). Enrollment was stopped early following a predetermined interim analysis that found the rate of near complete pathologic response to be significantly greater with the addition of pazopanib. As a planned secondary aim of the study, the outcome data for this cohort were analyzed. Eight-five eligible patients were randomly assigned to receive (regimen A) or not receive (regimen B) pazopanib in combination with ifosfamide and doxorubicin + preoperative radiotherapy followed by primary resection at week 13 and then further chemotherapy at week 25. As of December 31, 2021, at a median survivor follow-up of 3.3 years (range, 0.1-5.8 years), the 3-year event-free survival for all patients in the intent-to-treat analysis was 52.5% (95% CI, 34.8 to 70.2) for regimen A and 50.6% (95% CI, 32 to 69.2) for regimen B (P = .8677, log-rank test); the 3-year overall survival was 75.7% (95% CI, 59.7 to 91.7) for regimen A and 65.4% (95% CI, 48.1 to 82.7) for regimen B (P = .1919, log-rank test). Although the rate of near complete pathologic response was significantly greater with the addition of pazopanib, outcomes were not statistically significantly different between the two regimens.

FGFR1 gene fusions in a subset of pediatric mesenchymal tumors: Expanding the genetic spectrum of tumors sharing histologic overlap with infantile fibrosarcoma and "NTRK-rearranged" spindle cell neoplasms.

As the classification of kinase-driven spindle cell tumors continues to evolve, we describe the first series of pediatric mesenchymal tumors harboring FGFR1 gene fusions that share histologic overlap with infantile fibrosarcoma and "NTRK-rearranged" spindle cell neoplasms. Herein, we present three cases of FGFR1-rearranged pediatric mesenchymal tumors, including one case with FGFR1::PARD6B gene fusion and two cases with FGFR1::EBF2 gene fusion. The tumors involved infants ranging from 3 to 9 months in age with a male-to-female ratio of 2:1. All tumors involved the deep soft tissue of the gluteal, pelvic, or perirectal region. Histologically, the tumors comprised a cellular spindle cell neoplasm with primitive stellate cells, focal myxoid stroma, focal epithelioid features, no necrosis, and occasional mitotic figures (2-6 per 10 high-power field). By immunohistochemistry, the neoplastic cells focally expressed CD34 but lacked expression of S100 protein, SMA, desmin, myogenin, MyoD1, pan-TRK, and ALK. These three cases, including a case with long-term clinical follow-up, demonstrate that FGFR1 fusions occur in a subset of newly described pediatric kinase-driven mesenchymal tumors with locally aggressive behavior. Importantly, knowledge of these genetic alterations in this spectrum of pediatric tumors is key for diagnostic and targeted therapeutic purposes.

NR1D1::MAML1 epithelioid and spindle cell sarcoma mimicking pseudomyogenic hemangioendothelioma in core biopsy: A case report and review of the literature.

Epithelioid and spindle cell sarcomas with NR1D1::MAML1/2 gene fusions are rare and emerging entities. Only six cases of NR1D1-rearranged mesenchymal tumors have previously been reported in the literature; they are often characterized by an epithelioid morphology, at least focal pseudogland formation, prominent cytoplasmic vacuoles, and focal to diffuse immunohistochemical expression of keratin. We herein report the first case of an NR1D1::MAML1 epithelioid and spindle cell sarcoma with dual immunohistochemical expression of ERG and FOSB, mimicking a pseudomyogenic hemangioendothelioma (PHE) on core biopsy. The sarcoma arose in the left forearm of a 64-year-old man. Initial biopsy showed a mesenchymal neoplasm composed of epithelioid and spindle cells dispersed in myxoid stroma with scattered stromal neutrophils. The morphologic features, combined with the dual immunohistochemical expression of ERG and FOSB, initially mimicked PHE, representing an important potential diagnostic pitfall. The patient subsequently underwent a radical resection, which showed a much more diffuse epithelioid appearance with nested architecture and pseudogland formation. Next-generation sequencing was performed on the resection specimen, which revealed an NR1D1::MAML1 gene fusion, confirming the final diagnosis. Given the fully malignant potential of this tumor, knowledge and recognition of this rare entity are essential to ensure proper management, prevent misdiagnosis, and further characterize the clinical course of this emerging entity. Comprehensive molecular testing can help to identify these rare tumors and exclude the possibility of epithelioid mimics, including PHE.

Extraenteric Malignant Gastrointestinal Neuroectodermal Tumor-A Clinicopathologic and Molecular Genetic Study of 11 Cases.

Malignant gastrointestinal neuroectodermal tumors (MGNETs), also known as "gastrointestinal clear cell sarcoma-like tumors", are very rare, aggressive sarcomas characterized by enteric location, distinctive pathologic features, and EWSR1/FUS::ATF1/CREB1 fusions. Despite identical genetics, the clinicopathologic features of MGNET are otherwise quite different from those of clear cell sarcoma of soft parts. Only exceptional extraenteric MGNET (E-MGNET) has been reported. We report a series of 11 E-MGNETs, the largest to date. Cases diagnosed with MGNET and occurring in nonintestinal locations were retrieved. A clinical follow-up was obtained. The tumors occurred in 3 men and 8 women (range, 14-70 years of age; median, 33 years) and involved the soft tissues of the neck (3), shoulder (1), buttock (2), orbit (1), tongue/parapharyngeal space (1), urinary bladder (1), and falciform ligament/liver (1). Tumors showed morphologic features of enteric MGNET (small, relatively uniform, round to ovoid cells with round, regular nuclei containing small nucleoli growing in multinodular and vaguely lobular patterns, with solid, pseudoalveolar, and pseudopapillary architecture). Immunohistochemical results were S100 protein (11/11), SOX10 (11/11), synaptophysin (3/10), CD56 (7/9), CD117 (3/9), DOG1 (0/4), ALK (4/8), chromogranin A (0/10), HMB-45 (0/11), Melan-A (0/11), tyrosinase (0/4), and MiTF (0/11). Next-generation sequencing results were EWSR1::ATF1 (7 cases), EWSR1::CREB1 (3 cases), and EWSR1::PBX1 (1 case). The EWSR1::PBX1-positive tumor was similar to other cases, including osteoclast-like giant cells, and negative for myoepithelial markers. A clinical follow-up (range, 10-70 months; median, 34 months) showed 4 patients dead of disease (10.5, 12, 25, and 64 months after diagnosis), 1 patient alive with extensive metastases (43 months after diagnosis), 1 patient alive with persistent local disease (11 months after diagnosis), and 4 alive without disease (10, 47, 53, and 70 months after diagnosis). One case is too recent for the follow-up. The clinicopathologic and molecular genetic features of rare E-MGNET are essentially identical to those occurring in intestinal locations. Otherwise, typical E-MGNET may harbor EWSR1::PBX1, a finding previously unreported in this tumor type. As in enteric locations, the behavior of E-MGNET is aggressive, with metastases and/or death from disease in at least 50% of patients. E-MGNET should be distinguished from clear cell sarcoma of soft parts and other tumors with similar fusions. ALK expression appears to be a common feature of tumors harboring EWSR1/FUS::ATF1/CREB1 fusion but is unlikely to predict the therapeutic response to ALK inhibition. Future advances in our understanding of these unusual tumors will hopefully lead to improved nomenclature.

Beyond schwannomas and neurofibromas: a radiological and histopathological review of lesser-known benign lesions that arise in association with peripheral nerves.

Peripheral nerve sheath tumors comprise a significant percentage of both benign and malignant soft tissue tumors. The vast majority of these lesions are schwannomas and neurofibromas, which most radiologists are familiar with including the well-described multimodality imaging features. However, numerous additional often under-recognized benign entities associated with nerves exist. These rarer entities are becoming increasingly encountered with the proliferation of cross-sectional imaging, particularly magnetic resonance imaging (MRI). It is important for the radiologist to have a basic understanding of these entities as many have near-pathognomonic MR imaging features as well as specific clinical presentations that when interpreted in concert, often allows for a limited differential or single best diagnosis. The ability to provide a prospective, pre-intervention diagnosis based solely on imaging and clinical presentation is crucial as several of these entities are "do not touch" lesions, for which even a biopsy may have deleterious consequences. To our knowledge, the majority of these benign entities associated with nerves have only been described in scattered case reports or small case series. Therefore, the aim of this article is to provide a radiopathologic comprehensive review of these benign entities that arise in association with nerves with a focus on characteristic MRI features, unique histopathologic findings, and entity specific clinical exam findings/presentation.

Growth and differentiation of human induced pluripotent stem cell (hiPSC)-derived kidney organoids using fully synthetic peptide hydrogels.

Human induced pluripotent stem cell (hiPSC)-derived kidney organoids have prospective applications ranging from basic disease modelling to personalised medicine. However, there remains a necessity to refine the biophysical and biochemical parameters that govern kidney organoid formation. Differentiation within fully-controllable and physiologically relevant 3D growth environments will be critical to improving organoid reproducibility and maturation. Here, we matured hiPSC-derived kidney organoids within fully synthetic self-assembling peptide hydrogels (SAPHs) of variable stiffness (storage modulus, G'). The resulting organoids contained complex structures comparable to those differentiated within the animal-derived matrix, Matrigel. Single-cell RNA sequencing (scRNA-seq) was then used to compare organoids matured within SAPHs to those grown within Matrigel or at the air-liquid interface. A total of 13,179 cells were analysed, revealing 14 distinct clusters. Organoid compositional analysis revealed a larger proportion of nephron cell types within Transwell-derived organoids, while SAPH-derived organoids were enriched for stromal-associated cell populations. Notably, differentiation within a higher G' SAPH generated podocytes with more mature gene expression profiles. Additionally, maturation within a 3D microenvironment significantly reduced the derivation of off-target cell types, which are a known limitation of current kidney organoid protocols. This work demonstrates the utility of synthetic peptide-based hydrogels with a defined stiffness, as a minimally complex microenvironment for the selected differentiation of kidney organoids.

Single-cell multiomics reveals the complexity of TGFß signalling to chromatin in iPSC-derived kidney organoids.

TGFß1 plays a regulatory role in the determination of renal cell fate and the progression of renal fibrosis. Here we show an association between SMAD3 and the histone methyltransferase, EZH2, during cell differentiation; ChIP-seq revealed that SMAD3 and EZH2 co-occupy the genome in iPSCs and in iPSC-derived nephron progenitors. Through integration of single cell gene expression and epigenome profiling, we identified de novo ACTA2+ve/POSTN+ve myofibroblasts in kidney organoids treated with TGFß1, characterised by increased SMAD3-dependent cis chromatin accessibility and gene expression associated with fibroblast activation. We have identified fibrosis-associated regulons characterised by enrichment of SMAD3, AP1, the ETS family of transcription factors, and NUAK1, CREB3L1, and RARG, corresponding to enriched motifs at accessible loci identified by scATACseq. Treatment with the EZH2 specific inhibitor GSK343, blocked SMAD3-dependent cis co-accessibility and inhibited myofibroblast activation. This mechanism, through which TGFß signals directly to chromatin, represents a critical determinant of fibrotic, differentiated states.

A review of histopathologic features of pediatric autoimmune liver disease.

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1H, 13C, and 15N resonance assignments of a conserved putative cell wall binding domain from Enterococcus faecalis.

Enterococcus faecalis is a major causative agent of hospital acquired infections. The ability of E. faecalis to evade the host immune system is essential during pathogenesis, which has been shown to be dependent on the complete separation of daughter cells by peptidoglycan hydrolases. AtlE is a peptidoglycan hydrolase which is predicted to bind to the cell wall of E. faecalis, via six C-terminal repeat sequences. Here, we report the near complete assignment of one of these six repeats, as well as the predicted backbone structure and dynamics. This data will provide a platform for future NMR studies to explore the ligand recognition motif of AtlE and help to uncover its potential role in E. faecalis virulence.

Nonsebaceous lymphadenoma arising as a painless subcutaneous nodule on the eyebrow.

Salivary gland tumors can rarely present in skin excision specimens and can pose a diagnostic challenge to dermatopathologists. We present an exceptional case of a salivary gland type nonsebaceous lymphadenoma presenting as a painless subcutaneous nodule on the right medial eyebrow of a 16-year-old male, mimicking a primary cutaneous adnexal neoplasm. Histologic evaluation revealed a well-circumscribed to partially encapsulated nodule with a marked lymphoid infiltrate including reactive germinal centers. Within the lymphoid component was a central epithelial cystic neoplasm with tubuloglandular and basaloid differentiation. There was no myoepithelial component to suggest a chondroid syringoma. No sebaceous differentiation was present. The overall histopathological and immunohistochemical findings were consistent with a nonsebaceous lymphadenoma. Dermatopathologists should consider salivary gland type lymphadenoma as a differential diagnosis when encountering a subcutaneous lesion with lymphoid, cystic, glandular, and basaloid components.

Histologic characterization of paediatric mesenchymal neoplasms treated with kinase-targeted therapy.

AIMS: Recurrent alterations involving receptor tyrosine or cytoplasmic kinase genes have been described in soft-tissue neoplasms such as infantile fibrosarcoma (IFS) and inflammatory myofibroblastic tumour (IMT). Recent trials and regulatory approvals for targeted inhibitors against the kinase domains of these oncoproteins have allowed for increased use of targeted therapies. We aimed to characterize the histologic features of paediatric mesenchymal neoplasms with kinase alterations treated with targeted inhibitors. METHODS AND RESULTS: Eight patients with tyrosine kinase-altered mesenchymal neoplasms with pre- and posttreatment samples were identified. Tumours occurred in five females and three males with a median age at presentation of 6.5 years. Tumour sites were bone/somatic soft-tissue (n = 5) and viscera (n = 3). Pretreatment diagnoses were: IMT (n = 3), epithelioid inflammatory myofibroblastic sarcoma (n = 1), and descriptive diagnoses (n = 4) such as "kinase-driven spindle cell tumor." Fusions identified were ETV6::NTRK3 (n = 2), TPM3::NTRK1, SEPT7::BRAF, TFG::ROS1, KLC1::ALK, RANBP2::ALK, and MAP4::RAF1. Patients were treated with larotrectinib (n = 3), ALK or ALK/ROS1 inhibitors (n = 3), and MEK inhibitors (n = 2). Posttreatment tumours exhibited a striking decrease in cellularity (7/8) and the presence of collagenous stroma (7/8) with extensive glassy hyalinization (5/8). In two cases, abundant coarse or psammomatous calcifications were seen and in one case prominent perivascular hyalinization was noted. Residual viable tumour was seen in 3/8 cases (<5% in one case, and >75% in 2/8 cases). CONCLUSION: Mesenchymal neoplasms with tyrosine kinase alterations treated with targeted inhibitors show a pathologic response, which includes decreased cellularity and stromal hyalinization. The presence of these features may be helpful in assessing tumour response after targeted therapy.